Philippe Follana

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).

LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. METHODS Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. RESULTS Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. CONCLUSIONS In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text].

Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number.

BackgroundEGFR (epidermal growth factor receptor) gene gain assessed by FISH (fluorescence in situ hybridization) has been shown to be predictive of response to EGFR-targeted therapies in patients with non–small cell lung cancer. The aim or our study was to relate the EGFR gene copy number to therapeutic results in patients with metastatic colorectal cancer (CRC) treated with a cetuximab-containing regimen.MethodsForty-seven patients with metastatic CRC treated with a cetuximab-containing regimen between August 2004 and September 2006 were included in our study. EGFR status was assessed by immunohistochemistry (IHC) and by FISH on fixed paraffin-embedded sections of tumor specimens.ResultsBy IHC (n = 47), 39 patients (83%) had EGFR-positive tumors. EGFR gene copy gain was detected in 8 (19.5%) of 41 tumors. Neither EGFR expression assessed by IHC nor EGFR gene copy gain assessed by FISH were statistically significantly correlated with objective response rate, disease control rate, progression-free survival, and overall survival. Of the 33 patients whose tumors were FISH negative, 8 patients (24.2%) had a partial response, and 10 (30.3%) had stable disease.ConclusionsEGFR FISH analysis does not seem to be a sufficiently robust test for selecting candidate CRC patients for cetuximab therapy.

Free-flap head and neck reconstruction and quality of life: a 2-year prospective study.

Objectives: This prospective study was designed to evaluate quality of life (QOL) after free‐flap head and neck reconstruction.

Radical ablative surgery and radial forearm free flap (RFFF) reconstruction for patients with oral or oropharyngeal cancer: postoperative outcomes and oncologic and functional results

Conclusions. Radical ablative surgery and radial forearm free flap (RFFF) reconstruction provide promising oncologic and functional results in patients with oral or oropharyngeal cancer. Objectives. To assess the postoperative outcomes and the oncologic and functional results, with their main predictive factors, after radical ablative surgery and RFFF reconstruction for patients with oral or oropharyngeal cancer. Patients and methods. Between 2000 and 2006, we prospectively analyzed the postoperative, oncologic and functional outcomes of all previously untreated patients who underwent this type of surgery. Results. A total of 132 patients were enrolled in this study. There were three RFFF failures. The rate of surgical complications was 20%. The 5-year locoregional control and overall survival rates were 68% and 52%, respectively. Advanced age, high comorbidity index, elevated overall stage and tumoral involvement of the inner part of the cheek were correlated with a lower overall survival rate. A good functional result was obtained for oral diet, speech, mouth opening and aesthetic outcome in 87%, 80%, 86% and 88% of the patients, respectively. High comorbidity index, large flap surface, radiotherapy and tumoral involvement of the mobile tongue were significant predictors of poorer functional or aesthetic outcomes.

Oral cavity squamous cell carcinoma in 260 patients aged 80 years or more

PURPOSE We report the experience of two French cancer centers in the treatment of oral cavity squamous cell carcinoma (SCC) in patients aged 80 years. MATERIALS AND METHODS Two hundred and sixty patients aged 80 years with a primary oral cavity SCC were included in this retrospective analysis. RESULTS Sex ratio was near to 1. Tobacco or alcohol intoxication was the main risk factor for 66% of men and 16% of women and leukoplakia, lichen planus, or oral traumatism for 55% of women and 11% of men (p<0.0001). Two hundred patients received a loco-regional (LR) treatment with a curative intent (surgery and/or radiotherapy), 29 with a palliative intent and 31 did not receive a LR treatment. Curative treatments were initially planned to be adapted to age in 118 patients (59%). The median disease-specific survival (DSS) was 29 months. In multivariate analysis, the independent prognostic factors for DSS were stage (HR=0.42 [0.24-0.72]), age (HR=0.43 [0.24-0.75]) and performance status (HR=0.50 [0.27-0.95]). The median overall survival (OS) was 14 months. In multivariate analysis, the independent prognostic factors for OS were age (HR=0.52 [0.35-0.79]), stage (HR=0.56 [0.38-0.84]), tumor differentiation (HR=0.60 [0.33-0.93]) and performance status (HR=0.6 [0.37-0.97]). In patients treated with a curative intent, treatment adapted to age was not associated with a decreased overall survival or disease-specific survival as compared with the standard treatment. However, prophylactic lymph node treatment in stages I-II tumors decreased the rate of nodal recurrence from 38% to 6% (p=0.01). CONCLUSION This study emphasizes the need for prospective evaluation of standard and adapted schedules in elderly patients with oral cavity cancer.

Modeling of Salivary Production Recovery After Radiotherapy Using Mixed Models: Determination of Optimal Dose Constraint for IMRT Planning and Construction of Convenient Tools to Predict Salivary Function

PURPOSE The mathematical relationship between the dose to the parotid glands and salivary gland production needs to be elucidated. This study, which included data from patients included in a French prospective study assessing the benefit of intensity-modulated radiotherapy (RT), sought to elaborate a convenient and original model of salivary recovery. METHODS AND MATERIALS Between January 2001 and December 2004, 44 patients were included (35 with oropharyngeal and 9 with nasopharyngeal cancer). Of the 44 patients, 24 were treated with intensity-modulated RT, 17 with three-dimensional conformal RT, and 2 with two-dimensional RT. Stimulated salivary production was collected for </=24 months after RT. The data of salivary production, time of follow-up, and dose to parotid gland were modeled using a mixed model. Several models were developed to assess the best-fitting variable for the dose level to the parotid gland. RESULTS Models developed with the dose to the contralateral parotid fit the data slightly better than those with the dose to both parotids, suggesting that contralateral and ipsilateral parotid glands are not functionally equivalent even with the same dose level to the glands. The best predictive dose-value variable for salivary flow recovery was the volume of the contralateral parotid gland receiving >40 Gy. CONCLUSION The results of this study show that the recommendation of a dose constraint for intensity-modulated RT planning should be established at the volume of the contralateral parotid gland receiving >40 Gy rather than the mean dose. For complete salivary production recovery after 24 months, the volume of the contralateral parotid gland receiving >40 Gy should be <33%. Our results permitted us to establish two convenient tools to predict the saliva production recovery function according to the dose received by the contralateral parotid gland.

Second conservative treatment for ipsilateral breast cancer recurrence using high-dose rate interstitial brachytherapy: Preliminary clinical results and evaluation of patient satisfaction

PURPOSE To assess early clinical results and evaluate patient satisfaction in case of second conservative treatment (2nd CT) combining lumpectomy plus high-dose rate (HDR) interstitial brachytherapy for patients (pts) presenting with ipsilateral breast cancer recurrence (IBCR). METHODS AND MATERIALS From June 2005 to July 2009, 42 pts presenting with an IBCR underwent a second lumpectomy with intraoperative implantation of plastic tubes in the tumor bed. After performing the dose distribution analysis on the postimplant CT scan, a total dose of 34 Gy in 10 fractions over 5 consecutive days was delivered. Toxicity evaluation was based on the Common Terminology Criteria for Adverse Events v3.0 criteria. Applying a visual analogic scale (VAS) analysis, patient satisfaction regarding cosmetic result and 2nd CT possibility was performed after the end of brachytherapy. RESULTS Median followup was 21 months (range, 6-50 months) and median age at the time of local recurrence was 65 years (range, 30-85 years). Median delay between primary and recurrence was 11 years (range, 1-35 years). Median recurrence tumor size was 12 mm (range, 2-30 mm). Median number of plastic tubes and planes were nine (range, 5-12) and two (range, 1-3), respectively. Median clinical target volume was 68 cc (range, 31.2-146 cc). Second local control rate was 97%. Twenty-two pts (60%) developed complications. Cutaneous and subcutaneous fibrosis was the most frequent side effect. Median VAS satisfaction score regarding cosmetic result was 7 of 10 (range, 4-9), whereas median VAS satisfaction score for 2nd CT was 10 of 10 (range, 8-10). CONCLUSION A 2nd CT for IBCR using high-dose rate brachytherapy seems feasible with encouraging results in terms of second local control with an acceptable toxicity. Patient satisfaction regarding the possibility of second breast preservation should be considered.

Complex t(5;8) involving the CSPG2 and PTK2B genes in a case of dermatofibrosarcoma protuberans without the COL1A1-PDGFB fusion

Dermatofibrosarcoma protuberans (DFSP) is a rare, dermal neoplasm of intermediate malignancy. It is made of spindle-shaped tumor cells in a storiform pattern positive for CD34. Cytogenetically, DFSP cells are characterized by either supernumerary ring chromosomes composed of sequences derived from chromosomes 17 and 22 or more rarely of translocations t(17;22). These chromosomal rearrangements lead to the formation of a specific chimeric gene fusing COL1A1 to PDGFB. So far, the COL1A1-PDGFB fusion gene remains the sole fusion gene identified in DFSP. However, some observations suggest that genes, other than COL1A1 and PDGFB, might be involved in some DFSP cases. We report in this paper a DFSP case presenting as a unique chromosomal abnormality a complex translocation between chromosomes 5 and 8. This is the first report of a DFSP case where the lack of chromosomes 17 and 22 rearrangement and the absence of COL1A1-PDGFB fusion gene have been demonstrated. Using fluorescence in situ hybridization analysis, we showed that the CSPG2 gene at 5q14.3 and the PTK2B gene at 8p21.2 were disrupted by this rearrangement. Although rare, the existence of cases of DFSP negative for the COL1A1-PDGFB fusion has to be taken in consideration when performing molecular diagnosis for a tumor suspected to be a DFSP.

Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study

PURPOSE Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigators choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.

Prognostic factors in 401 elderly women with metastatic breast cancer.

Background: Elderly patients with metastatic breast cancer have a prognosis and outcome that may be dependent on a host of factors. Patients and Methods: We retrospectively analyzed 401 female breast cancer patients who developed metastatic disease after the age of 70 years in order to define potential prognostic factors for specific survival at the time of first recurrence. Results: With a median follow-up of 60 months from the time of recurrence, the median specific survival was 21.0 months (95% CI 17.0-23.0). In multivariate analysis we demonstrated that negative hormonal receptor status (p = 0.002), presence of positive lymph nodes at initial cancer diagnosis (hazard ratio, HR = 1.37; 95% CI 1.07-1.75; p = 0.01), site of metastasis (p < 10-4) and metastasis-free interval (HR = 0.99; 95% CI 0.95-0.99; p = 0.008) constituted unfavorable independent prognostic factors able to predict specific survival from the time of metastatic occurrence. Age at initial diagnosis, Scarff-Bloom Richardson grade and adjuvant treatments were significant only in univariate analysis. Conclusion: These survival prognostic factors associated with the use of a specific geriatric questionnaire to assess frailty may assist physicians in evaluating the patients survival potential and choose a tailored treatment to this cancer population.